{"gene":"SRP72","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":2016,"finding":"Crystal structures of the SRP68 protein-binding domain (PBD) in complex with SRP72-PBD, and of the SRP72-RNA-binding domain (RBD) bound to the SRP S domain, revealed that SRP72-PBD contains a tetratricopeptide repeat (TPR) that binds an extended linear motif of SRP68 with high affinity; SRP72-RBD is a flexible peptide that crawls along the 5e- and 5f-loops of SRP RNA, with a conserved tryptophan inserting into the 5e-loop to form a novel K+-turn stabilized by a potassium ion; SRP72-RBD also remodels the 5f-loop involved in ribosome binding. Docking of the S domain into cryo-EM density maps identified multiple contact sites between SRP68/72 and the ribosome.","method":"X-ray crystallography, cryo-EM docking, structural analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures with functional validation of RNA-binding interactions, novel K+-turn mechanism structurally defined, cryo-EM docking corroborates ribosome contacts","pmids":["27899666"],"is_preprint":false},{"year":2017,"finding":"Crystal structures of human apo-SRP72 and the SRP68/72 complex showed that the SRP68-binding domain of SRP72 contains four atypical TPR repeats and a flexible C-terminal cap; apo-SRP72 exists as a homodimer in solution, and homodimer dissociation plus a pronounced conformational change in the C-terminal cap are required for SRP68/72 heterodimer formation. A 23-residue polypeptide of SRP68 is sufficient for tight binding to SRP72 via an unusually hydrophobic extended surface. Mutagenesis of cancer-associated residues disrupted SRP68-SRP72 interaction and their co-localization with ER.","method":"X-ray crystallography (2.91 Å apo-SRP72; 1.7 Å complex), biophysical assays, site-directed mutagenesis, co-localization in mammalian cells","journal":"Journal of molecular cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution crystal structures corroborated by mutagenesis and cell-based co-localization, multiple orthogonal methods in one study","pmids":["28369529"],"is_preprint":false},{"year":2005,"finding":"A 63-amino-acid region near the C-terminus of SRP72 binds SRP RNA with high affinity; within this region a 56-residue RNA-binding domain contains the conserved consensus PDPXRWLPXXER. Chymotrypsin treatment of this fragment abolishes RNA-binding activity. SRP72 binds specifically to the moderately conserved portion of SRP RNA helix 5, as shown by sucrose gradient centrifugation and filter-binding assays with mutant SRP RNAs. The NH2-terminal region contains nine TPR-like repeats predicted to interact with SRP or ribosomal proteins.","method":"Recombinant protein expression, limited proteolysis, filter-binding assay, sucrose gradient centrifugation, SRP RNA mutagenesis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro biochemical reconstitution with domain mapping, proteolysis-based functional validation, RNA mutant panel; single lab but multiple orthogonal methods","pmids":["15588816"],"is_preprint":false},{"year":2006,"finding":"SRP68 binds recombinant SRP72 and SRP RNA in vitro. The RNA-binding domain of SRP68 spans residues 52–252, while a 94-amino-acid C-terminal region of SRP68 mediates binding to SRP72. The SRP68-SRP72 interaction is stable at elevated salt concentrations and engages approximately 150 N-terminal residues of SRP72, which lie within a predicted tandem array of four TPR-like motifs forming a superhelical groove.","method":"Recombinant protein expression in E. coli, pulldown/binding assays, proteolytic fragment mapping","journal":"Protein science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro binding assays with defined domain fragments, single lab, multiple domain-mapping experiments","pmids":["16672232"],"is_preprint":false},{"year":2007,"finding":"Systematic mutagenesis of 18 positions in SRP RNA helices 5, 6, and 8 showed that binding of the SRP68/72 heterodimer is impaired by mutations throughout the large SRP RNA domain, with strongest effects in helix 5 (residues 222–231) and helix 8 (residues 176–191 and 202–214). In contrast, a 7.4-kDa RNA-binding fragment of SRP72 alone is diminished primarily by mutations in helix 5 (residues 120–128) and is unaffected by deletion of helices 6 and 8, demonstrating that SRP72 contacts only the 5ef region of the large SRP RNA domain.","method":"Competitive double-filter binding assay with purified proteins and 18 mutant SRP RNAs","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic RNA mutagenesis with quantitative binding assay, single lab, but comprehensive mutant panel","pmids":["18347438"],"is_preprint":false},{"year":2008,"finding":"The 5e motif of human SRP RNA contains the conserved adenosine A240 that is essential for SRP72 binding; A240G or A240C substitutions dramatically reduce binding of the SRP72 C-terminal fragment (72c'), and full-length SRP72 cannot form a complex with A240G-mutant SRP RNA. Chimera experiments with human and archaeal SRP RNAs confirmed that the 5e helical section alone contains the SRP72 binding site and no other SRP RNA regions are required.","method":"Chimeric SRP RNA construction, site-directed mutagenesis, filter-binding assay, competitive binding with RNA fragments","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis combined with chimera and competition assays; single lab, multiple orthogonal approaches","pmids":["18441046"],"is_preprint":false},{"year":2010,"finding":"The minimal SRP72 RNA-binding region spans residues 545–585 and requires both a lysine-rich cluster (K552–K561) and the conserved PDPXRWLPXXER motif (W577 in particular). Site-directed mutagenesis of both regions impairs SRP RNA complex formation. Molecular modeling and native gel electrophoresis showed that the 5e motif forms a kink-turn, with conserved A240 likely protruding into a groove of the SRP72 RNA-binding domain.","method":"Site-directed mutagenesis, native PAGE, molecular modeling, chymotryptic digestion mapping","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with binding readout plus structural modeling; single lab, multiple methods but modeling is partly computational","pmids":["21073748"],"is_preprint":false},{"year":2012,"finding":"SRP68/72 heterodimers (but not the intact SRP complex) bind the histone H4 tail peptide in vitro, and this binding is inhibited by H4R3 methylation. SRP68 and SRP72 associate with chromatin in vivo, regulated by PRMT5 and PRMT1. When tethered to a reporter gene via a heterologous DNA-binding domain, both SRP68 and SRP72 activate transcription, identifying a chromatin/transcriptional regulatory function for the SRP68/72 heterodimer distinct from its SRP role.","method":"Proteomic pulldown with histone H4 tail peptides, Co-IP, chromatin association assay, transcriptional reporter assay, genome-wide occupancy analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal pulldown and chromatin assays with functional transcriptional readout; single lab, multiple orthogonal methods","pmids":["23048028"],"is_preprint":false},{"year":2012,"finding":"Heterozygous SRP72 mutations in familial aplastic anemia/MDS patients cause mislocalization of the SRP72 protein within mammalian cells (transfection experiments), and one SRP72 variant fails to fully associate with the SRP RNA component as shown by co-immunoprecipitation of epitope-tagged SRP72.","method":"Transfection of mutant constructs in mammalian cells (localization), co-immunoprecipitation with epitope-tagged SRP72","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and cell-based localization in a disease context; replicated across two mutation families but single lab, limited mechanistic depth","pmids":["22541560"],"is_preprint":false},{"year":2010,"finding":"IL-1β stimulation of Jurkat cells causes up-regulation of SRP72 protein expression and SRP72 phosphorylation; pharmacological inhibition of ERK1/2 or p38α/β MAPK pathways suppresses both the IL-1β-induced expression and phosphorylation of SRP72, placing SRP72 phosphorylation downstream of MAPK signaling.","method":"Immunoprecipitation, immunoprecipitation-Western blotting, real-time PCR, MAPK inhibitor treatment in Jurkat cells","journal":"The Journal of biological chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pharmacological inhibitors only (no direct kinase-substrate assay), no identification of specific phosphorylation sites","pmids":["20729213"],"is_preprint":false},{"year":2019,"finding":"Heterozygous loss of Srp72 in mice leads to transcriptional down-regulation of genes encoding secreted factors (cytokines and receptors) in hematopoietic cells, consistent with SRP72's role in targeting secretory proteins to the ER; however, no major hematological disorder phenotype was observed.","method":"Srp72 null mouse model, flow cytometry, bone marrow transplantation, gene expression analysis","journal":"European journal of haematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mouse model with gene expression analysis providing mechanistic link between SRP72 dosage and secretory protein production; single lab","pmids":["31254415"],"is_preprint":false}],"current_model":"SRP72 is the largest subunit of the mammalian signal recognition particle (SRP): its C-terminal RNA-binding domain (residues ~545–585) contacts the K+-turn of SRP RNA helix 5e via a conserved PDPXRWLPXXER motif (with W577 critical) and remodels the adjacent 5f-loop involved in ribosome binding, while its N-terminal TPR domain forms a heterodimer with SRP68 (requiring dissociation of an SRP72 homodimer and a conformational change in a C-terminal cap), and the SRP68/72 heterodimer additionally functions in the nucleus as a histone H4-binding, transcriptional regulatory complex whose chromatin association is controlled by PRMT1/PRMT5-mediated H4R3 methylation."},"narrative":{"mechanistic_narrative":"SRP72 is the largest subunit of the signal recognition particle (SRP), where it bridges SRP RNA and the SRP68 partner protein to support co-translational targeting of secretory proteins to the ER [PMID:27899666, PMID:15588816]. Its C-terminal RNA-binding region (minimally residues 545–585) crawls along the 5e- and 5f-loops of the large SRP RNA domain: a lysine-rich cluster and the conserved PDPXRWLPXXER motif—with W577 inserting into the 5e-loop—stabilize a potassium-dependent K-turn anchored by the conserved adenosine A240, while remodeling the 5f-loop implicated in ribosome binding [PMID:27899666, PMID:18441046, PMID:21073748]. Binding specificity is restricted to the 5ef region of SRP RNA, as the isolated SRP72 RNA-binding fragment is sensitive only to helix-5 mutations [PMID:18347438]. The N-terminal domain comprises atypical tetratricopeptide (TPR) repeats forming a superhelical groove that captures an extended linear peptide of SRP68; heterodimer formation requires dissociation of an apo-SRP72 homodimer and a conformational change in a C-terminal cap [PMID:27899666, PMID:28369529, PMID:16672232]. Beyond the SRP, the SRP68/72 heterodimer—but not intact SRP—binds the histone H4 tail, associates with chromatin under control of PRMT1/PRMT5-mediated H4R3 methylation, and activates transcription when tethered to a reporter, defining a distinct nuclear regulatory function [PMID:23048028]. Heterozygous SRP72 mutations cause familial aplastic anemia/myelodysplastic syndrome, with disease variants disrupting SRP68 binding, ER co-localization, and SRP RNA association [PMID:28369529, PMID:22541560].","teleology":[{"year":2005,"claim":"Established that SRP72 is a bifunctional protein with a discrete C-terminal RNA-binding module and an N-terminal TPR array, answering where in the protein RNA contact occurs.","evidence":"Recombinant fragment expression, limited proteolysis, filter-binding and sucrose-gradient assays with SRP RNA mutants","pmids":["15588816"],"confidence":"High","gaps":["Atomic-resolution geometry of RNA contact not resolved","TPR partner not yet identified biochemically"]},{"year":2006,"claim":"Defined the SRP68–SRP72 interaction interface, showing the N-terminal TPR-like motifs of SRP72 form the SRP68 docking surface.","evidence":"Recombinant binding/pulldown assays with defined domain fragments of SRP68 and SRP72","pmids":["16672232"],"confidence":"Medium","gaps":["No structure of the complex","Stoichiometry and conformational requirements unknown"]},{"year":2007,"claim":"Distinguished SRP72-alone RNA contacts from those of the SRP68/72 heterodimer, mapping SRP72 specifically to the 5ef region of the large SRP RNA domain.","evidence":"Competitive double-filter binding with 18 SRP RNA helix mutants and purified proteins","pmids":["18347438"],"confidence":"Medium","gaps":["Single-lab biochemistry","Functional consequence on targeting not measured"]},{"year":2008,"claim":"Pinpointed conserved adenosine A240 in the 5e motif as essential for SRP72 binding, narrowing the recognition determinant to a single helical section.","evidence":"Chimeric human/archaeal SRP RNA constructs, site-directed mutagenesis, filter-binding and competition assays","pmids":["18441046"],"confidence":"Medium","gaps":["Structural basis of A240 recognition inferred, not visualized","Single lab"]},{"year":2010,"claim":"Resolved the minimal RNA-binding peptide and the sequence elements (lysine cluster, PDPXRWLPXXER motif, W577) needed for SRP RNA engagement, and modeled the 5e kink-turn.","evidence":"Site-directed mutagenesis with binding readout, native PAGE, molecular modeling, chymotryptic mapping","pmids":["21073748"],"confidence":"Medium","gaps":["Kink-turn model partly computational","K+ dependence not yet demonstrated"]},{"year":2012,"claim":"Uncovered a moonlighting nuclear role: the SRP68/72 heterodimer binds the histone H4 tail, occupies chromatin under PRMT control, and can activate transcription, separating this function from the SRP.","evidence":"Histone tail peptide pulldown, Co-IP, chromatin association, transcriptional reporter, genome-wide occupancy","pmids":["23048028"],"confidence":"Medium","gaps":["Direct transcriptional targets not defined","Mechanism of nuclear versus cytoplasmic partitioning unknown"]},{"year":2012,"claim":"Linked SRP72 to human disease, showing heterozygous mutations in familial aplastic anemia/MDS mislocalize the protein and impair SRP RNA association.","evidence":"Mutant construct transfection (localization) and Co-IP of epitope-tagged SRP72 in mammalian cells","pmids":["22541560"],"confidence":"Medium","gaps":["Mechanistic path from SRP defect to hematopoietic failure unresolved","Limited mechanistic depth, single lab"]},{"year":2016,"claim":"Provided the structural mechanism: SRP72-TPR binds an extended SRP68 motif, and the flexible SRP72-RBD crawls along the 5e/5f loops with a tryptophan forming a K+-stabilized turn while remodeling the ribosome-binding 5f-loop.","evidence":"X-ray crystallography of SRP68-PBD/SRP72-PBD and SRP72-RBD/S domain, cryo-EM docking onto ribosome maps","pmids":["27899666"],"confidence":"High","gaps":["Dynamics of RBD crawling during the targeting cycle not captured","Ribosome contacts inferred from docking"]},{"year":2017,"claim":"Showed the conformational logic of heterodimer assembly—apo-SRP72 is a homodimer whose dissociation and C-terminal cap rearrangement enable SRP68 capture—and connected cancer-associated residues to interface disruption.","evidence":"Crystal structures of apo-SRP72 and SRP68/72 complex, biophysics, mutagenesis, cell co-localization","pmids":["28369529"],"confidence":"High","gaps":["Trigger for homodimer-to-heterodimer transition in cells unknown","Functional role of homodimer state undefined"]},{"year":2019,"claim":"Connected SRP72 gene dosage to secretory output in vivo: heterozygous Srp72 loss down-regulates genes encoding secreted factors in hematopoietic cells.","evidence":"Srp72 null mouse model, flow cytometry, bone marrow transplantation, gene expression analysis","pmids":["31254415"],"confidence":"Medium","gaps":["No overt hematological phenotype, leaving disease mechanism incomplete","Whether transcriptional changes are direct (chromatin role) or indirect (ER targeting) not resolved"]},{"year":null,"claim":"How SRP72's cytoplasmic SRP function and its nuclear chromatin/transcriptional function are coordinated, and how either is perturbed to cause bone marrow failure, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No mechanism connecting SRP RNA binding defects to hematopoietic disease","Regulation of SRP68/72 nuclear partitioning unknown","Phosphorylation sites and functional consequence of MAPK-dependent modification undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,4,5,6]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[7]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[7]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,10]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,10]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7]}],"complexes":["signal recognition particle (SRP)","SRP68/72 heterodimer"],"partners":["SRP68","PRMT1","PRMT5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O76094","full_name":"Signal recognition particle subunit SRP72","aliases":["Signal recognition particle 72 kDa protein"],"length_aa":671,"mass_kda":74.6,"function":"Component of the signal recognition particle (SRP) complex, a ribonucleoprotein complex that mediates the cotranslational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER) (PubMed:34020957). The SRP complex interacts with the signal sequence in nascent secretory and membrane proteins and directs them to the membrane of the ER (PubMed:34020957). The SRP complex targets the ribosome-nascent chain complex to the SRP receptor (SR), which is anchored in the ER, where SR compaction and GTPase rearrangement drive cotranslational protein translocation into the ER (PubMed:34020957). Binds the signal recognition particle RNA (7SL RNA) in presence of SRP68 (PubMed:21073748, PubMed:27899666). Can bind 7SL RNA with low affinity (PubMed:21073748, PubMed:27899666). The SRP complex possibly participates in the elongation arrest function (By similarity)","subcellular_location":"Cytoplasm; Endoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/O76094/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SRP72","classification":"Common Essential","n_dependent_lines":1171,"n_total_lines":1208,"dependency_fraction":0.9693708609271523},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000174780","cell_line_id":"CID001597","localizations":[{"compartment":"cytoplasmic","grade":3}],"interactors":[{"gene":"CTCF","stoichiometry":10.0},{"gene":"RPL19","stoichiometry":10.0},{"gene":"RPL35","stoichiometry":10.0},{"gene":"RPL4","stoichiometry":10.0},{"gene":"RPS16","stoichiometry":10.0},{"gene":"SRP19","stoichiometry":10.0},{"gene":"SRP68","stoichiometry":10.0},{"gene":"SERBP1","stoichiometry":10.0},{"gene":"RPS6","stoichiometry":10.0},{"gene":"RPS25","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001597","total_profiled":1310},"omim":[{"mim_id":"614675","title":"BONE MARROW FAILURE SYNDROME 1; BMFS1","url":"https://www.omim.org/entry/614675"},{"mim_id":"604858","title":"SIGNAL RECOGNITION PARTICLE, 68-KD; SRP68","url":"https://www.omim.org/entry/604858"},{"mim_id":"604857","title":"SIGNAL RECOGNITION PARTICLE, 54-KD; SRP54","url":"https://www.omim.org/entry/604857"},{"mim_id":"602123","title":"CALCIUM/CALMODULIN-DEPENDENT PROTEIN KINASE II-GAMMA; CAMK2G","url":"https://www.omim.org/entry/602123"},{"mim_id":"602122","title":"SIGNAL RECOGNITION PARTICLE, 72-KD; SRP72","url":"https://www.omim.org/entry/602122"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SRP72"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O76094","domains":[{"cath_id":"1.25.40","chopping":"431-505","consensus_level":"medium","plddt":92.3105,"start":431,"end":505}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O76094","model_url":"https://alphafold.ebi.ac.uk/files/AF-O76094-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O76094-F1-predicted_aligned_error_v6.png","plddt_mean":81.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SRP72","jax_strain_url":"https://www.jax.org/strain/search?query=SRP72"},"sequence":{"accession":"O76094","fasta_url":"https://rest.uniprot.org/uniprotkb/O76094.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O76094/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O76094"}},"corpus_meta":[{"pmid":"22541560","id":"PMC_22541560","title":"Exome sequencing identifies autosomal-dominant SRP72 mutations associated with familial aplasia and myelodysplasia.","date":"2012","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22541560","citation_count":87,"is_preprint":false},{"pmid":"27899666","id":"PMC_27899666","title":"Structures of human SRP72 complexes provide insights into SRP RNA remodeling and ribosome interaction.","date":"2016","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/27899666","citation_count":28,"is_preprint":false},{"pmid":"15588816","id":"PMC_15588816","title":"Identification of an RNA-binding domain in human SRP72.","date":"2005","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15588816","citation_count":21,"is_preprint":false},{"pmid":"20729213","id":"PMC_20729213","title":"Inhibitors of MAPK pathway ERK1/2 or p38 prevent the IL-1{beta}-induced up-regulation of SRP72 autoantigen in Jurkat cells.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20729213","citation_count":21,"is_preprint":false},{"pmid":"28369529","id":"PMC_28369529","title":"Human apo-SRP72 and SRP68/72 complex structures reveal the molecular basis of protein translocation.","date":"2017","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28369529","citation_count":17,"is_preprint":false},{"pmid":"23048028","id":"PMC_23048028","title":"A novel histone H4 arginine 3 methylation-sensitive histone H4 binding activity and transcriptional regulatory function for signal recognition particle subunits SRP68 and SRP72.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23048028","citation_count":17,"is_preprint":false},{"pmid":"16672232","id":"PMC_16672232","title":"Protein SRP68 of human signal recognition particle: identification of the RNA and SRP72 binding domains.","date":"2006","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/16672232","citation_count":17,"is_preprint":false},{"pmid":"31254415","id":"PMC_31254415","title":"Heterozygous loss of Srp72 in mice is not associated with major hematological phenotypes.","date":"2019","source":"European journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/31254415","citation_count":9,"is_preprint":false},{"pmid":"18347438","id":"PMC_18347438","title":"Identification of the RNA binding regions of SRP68/72 and SRP72 by systematic mutagenesis of human SRP RNA.","date":"2007","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/18347438","citation_count":9,"is_preprint":false},{"pmid":"18441046","id":"PMC_18441046","title":"The 5e motif of eukaryotic signal recognition particle RNA contains a conserved adenosine for the binding of SRP72.","date":"2008","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/18441046","citation_count":9,"is_preprint":false},{"pmid":"21073748","id":"PMC_21073748","title":"Identification of amino acid residues in protein SRP72 required for binding to a kinked 5e motif of the human signal recognition particle RNA.","date":"2010","source":"BMC molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21073748","citation_count":8,"is_preprint":false},{"pmid":"37176611","id":"PMC_37176611","title":"A Novel Constitutional t(3;8)(p26;q21) and ANKRD26 and SRP72 Variants in a Child with Myelodysplastic Neoplasm: Clinical Implications.","date":"2023","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37176611","citation_count":2,"is_preprint":false},{"pmid":"41472573","id":"PMC_41472573","title":"A De Novo Splicing Mutation of SRP72 in Bone Marrow Failure Syndrome Type 1: Case Report and Review of the Literature.","date":"2026","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41472573","citation_count":1,"is_preprint":false},{"pmid":"40922878","id":"PMC_40922878","title":"A 14-Year-Old Male Patient With Bone Marrow Failure Syndrome, Without Deafness, Caused by a Novel SRP72 Mutation Inherited From His Father: A Case Report.","date":"2025","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/40922878","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8611,"output_tokens":3240,"usd":0.037216,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10732,"output_tokens":3480,"usd":0.07033,"stage2_stop_reason":"end_turn"},"total_usd":0.107546,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structures of the SRP68 protein-binding domain (PBD) in complex with SRP72-PBD, and of the SRP72-RNA-binding domain (RBD) bound to the SRP S domain, revealed that SRP72-PBD contains a tetratricopeptide repeat (TPR) that binds an extended linear motif of SRP68 with high affinity; SRP72-RBD is a flexible peptide that crawls along the 5e- and 5f-loops of SRP RNA, with a conserved tryptophan inserting into the 5e-loop to form a novel K+-turn stabilized by a potassium ion; SRP72-RBD also remodels the 5f-loop involved in ribosome binding. Docking of the S domain into cryo-EM density maps identified multiple contact sites between SRP68/72 and the ribosome.\",\n      \"method\": \"X-ray crystallography, cryo-EM docking, structural analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures with functional validation of RNA-binding interactions, novel K+-turn mechanism structurally defined, cryo-EM docking corroborates ribosome contacts\",\n      \"pmids\": [\"27899666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structures of human apo-SRP72 and the SRP68/72 complex showed that the SRP68-binding domain of SRP72 contains four atypical TPR repeats and a flexible C-terminal cap; apo-SRP72 exists as a homodimer in solution, and homodimer dissociation plus a pronounced conformational change in the C-terminal cap are required for SRP68/72 heterodimer formation. A 23-residue polypeptide of SRP68 is sufficient for tight binding to SRP72 via an unusually hydrophobic extended surface. Mutagenesis of cancer-associated residues disrupted SRP68-SRP72 interaction and their co-localization with ER.\",\n      \"method\": \"X-ray crystallography (2.91 Å apo-SRP72; 1.7 Å complex), biophysical assays, site-directed mutagenesis, co-localization in mammalian cells\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution crystal structures corroborated by mutagenesis and cell-based co-localization, multiple orthogonal methods in one study\",\n      \"pmids\": [\"28369529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A 63-amino-acid region near the C-terminus of SRP72 binds SRP RNA with high affinity; within this region a 56-residue RNA-binding domain contains the conserved consensus PDPXRWLPXXER. Chymotrypsin treatment of this fragment abolishes RNA-binding activity. SRP72 binds specifically to the moderately conserved portion of SRP RNA helix 5, as shown by sucrose gradient centrifugation and filter-binding assays with mutant SRP RNAs. The NH2-terminal region contains nine TPR-like repeats predicted to interact with SRP or ribosomal proteins.\",\n      \"method\": \"Recombinant protein expression, limited proteolysis, filter-binding assay, sucrose gradient centrifugation, SRP RNA mutagenesis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro biochemical reconstitution with domain mapping, proteolysis-based functional validation, RNA mutant panel; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"15588816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SRP68 binds recombinant SRP72 and SRP RNA in vitro. The RNA-binding domain of SRP68 spans residues 52–252, while a 94-amino-acid C-terminal region of SRP68 mediates binding to SRP72. The SRP68-SRP72 interaction is stable at elevated salt concentrations and engages approximately 150 N-terminal residues of SRP72, which lie within a predicted tandem array of four TPR-like motifs forming a superhelical groove.\",\n      \"method\": \"Recombinant protein expression in E. coli, pulldown/binding assays, proteolytic fragment mapping\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro binding assays with defined domain fragments, single lab, multiple domain-mapping experiments\",\n      \"pmids\": [\"16672232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Systematic mutagenesis of 18 positions in SRP RNA helices 5, 6, and 8 showed that binding of the SRP68/72 heterodimer is impaired by mutations throughout the large SRP RNA domain, with strongest effects in helix 5 (residues 222–231) and helix 8 (residues 176–191 and 202–214). In contrast, a 7.4-kDa RNA-binding fragment of SRP72 alone is diminished primarily by mutations in helix 5 (residues 120–128) and is unaffected by deletion of helices 6 and 8, demonstrating that SRP72 contacts only the 5ef region of the large SRP RNA domain.\",\n      \"method\": \"Competitive double-filter binding assay with purified proteins and 18 mutant SRP RNAs\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic RNA mutagenesis with quantitative binding assay, single lab, but comprehensive mutant panel\",\n      \"pmids\": [\"18347438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The 5e motif of human SRP RNA contains the conserved adenosine A240 that is essential for SRP72 binding; A240G or A240C substitutions dramatically reduce binding of the SRP72 C-terminal fragment (72c'), and full-length SRP72 cannot form a complex with A240G-mutant SRP RNA. Chimera experiments with human and archaeal SRP RNAs confirmed that the 5e helical section alone contains the SRP72 binding site and no other SRP RNA regions are required.\",\n      \"method\": \"Chimeric SRP RNA construction, site-directed mutagenesis, filter-binding assay, competitive binding with RNA fragments\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis combined with chimera and competition assays; single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"18441046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The minimal SRP72 RNA-binding region spans residues 545–585 and requires both a lysine-rich cluster (K552–K561) and the conserved PDPXRWLPXXER motif (W577 in particular). Site-directed mutagenesis of both regions impairs SRP RNA complex formation. Molecular modeling and native gel electrophoresis showed that the 5e motif forms a kink-turn, with conserved A240 likely protruding into a groove of the SRP72 RNA-binding domain.\",\n      \"method\": \"Site-directed mutagenesis, native PAGE, molecular modeling, chymotryptic digestion mapping\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with binding readout plus structural modeling; single lab, multiple methods but modeling is partly computational\",\n      \"pmids\": [\"21073748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SRP68/72 heterodimers (but not the intact SRP complex) bind the histone H4 tail peptide in vitro, and this binding is inhibited by H4R3 methylation. SRP68 and SRP72 associate with chromatin in vivo, regulated by PRMT5 and PRMT1. When tethered to a reporter gene via a heterologous DNA-binding domain, both SRP68 and SRP72 activate transcription, identifying a chromatin/transcriptional regulatory function for the SRP68/72 heterodimer distinct from its SRP role.\",\n      \"method\": \"Proteomic pulldown with histone H4 tail peptides, Co-IP, chromatin association assay, transcriptional reporter assay, genome-wide occupancy analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal pulldown and chromatin assays with functional transcriptional readout; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"23048028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Heterozygous SRP72 mutations in familial aplastic anemia/MDS patients cause mislocalization of the SRP72 protein within mammalian cells (transfection experiments), and one SRP72 variant fails to fully associate with the SRP RNA component as shown by co-immunoprecipitation of epitope-tagged SRP72.\",\n      \"method\": \"Transfection of mutant constructs in mammalian cells (localization), co-immunoprecipitation with epitope-tagged SRP72\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and cell-based localization in a disease context; replicated across two mutation families but single lab, limited mechanistic depth\",\n      \"pmids\": [\"22541560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-1β stimulation of Jurkat cells causes up-regulation of SRP72 protein expression and SRP72 phosphorylation; pharmacological inhibition of ERK1/2 or p38α/β MAPK pathways suppresses both the IL-1β-induced expression and phosphorylation of SRP72, placing SRP72 phosphorylation downstream of MAPK signaling.\",\n      \"method\": \"Immunoprecipitation, immunoprecipitation-Western blotting, real-time PCR, MAPK inhibitor treatment in Jurkat cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pharmacological inhibitors only (no direct kinase-substrate assay), no identification of specific phosphorylation sites\",\n      \"pmids\": [\"20729213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Heterozygous loss of Srp72 in mice leads to transcriptional down-regulation of genes encoding secreted factors (cytokines and receptors) in hematopoietic cells, consistent with SRP72's role in targeting secretory proteins to the ER; however, no major hematological disorder phenotype was observed.\",\n      \"method\": \"Srp72 null mouse model, flow cytometry, bone marrow transplantation, gene expression analysis\",\n      \"journal\": \"European journal of haematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mouse model with gene expression analysis providing mechanistic link between SRP72 dosage and secretory protein production; single lab\",\n      \"pmids\": [\"31254415\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SRP72 is the largest subunit of the mammalian signal recognition particle (SRP): its C-terminal RNA-binding domain (residues ~545–585) contacts the K+-turn of SRP RNA helix 5e via a conserved PDPXRWLPXXER motif (with W577 critical) and remodels the adjacent 5f-loop involved in ribosome binding, while its N-terminal TPR domain forms a heterodimer with SRP68 (requiring dissociation of an SRP72 homodimer and a conformational change in a C-terminal cap), and the SRP68/72 heterodimer additionally functions in the nucleus as a histone H4-binding, transcriptional regulatory complex whose chromatin association is controlled by PRMT1/PRMT5-mediated H4R3 methylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SRP72 is the largest subunit of the signal recognition particle (SRP), where it bridges SRP RNA and the SRP68 partner protein to support co-translational targeting of secretory proteins to the ER [#0, #2]. Its C-terminal RNA-binding region (minimally residues 545\\u2013585) crawls along the 5e- and 5f-loops of the large SRP RNA domain: a lysine-rich cluster and the conserved PDPXRWLPXXER motif\\u2014with W577 inserting into the 5e-loop\\u2014stabilize a potassium-dependent K-turn anchored by the conserved adenosine A240, while remodeling the 5f-loop implicated in ribosome binding [#0, #5, #6]. Binding specificity is restricted to the 5ef region of SRP RNA, as the isolated SRP72 RNA-binding fragment is sensitive only to helix-5 mutations [#4]. The N-terminal domain comprises atypical tetratricopeptide (TPR) repeats forming a superhelical groove that captures an extended linear peptide of SRP68; heterodimer formation requires dissociation of an apo-SRP72 homodimer and a conformational change in a C-terminal cap [#0, #1, #3]. Beyond the SRP, the SRP68/72 heterodimer\\u2014but not intact SRP\\u2014binds the histone H4 tail, associates with chromatin under control of PRMT1/PRMT5-mediated H4R3 methylation, and activates transcription when tethered to a reporter, defining a distinct nuclear regulatory function [#7]. Heterozygous SRP72 mutations cause familial aplastic anemia/myelodysplastic syndrome, with disease variants disrupting SRP68 binding, ER co-localization, and SRP RNA association [#1, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that SRP72 is a bifunctional protein with a discrete C-terminal RNA-binding module and an N-terminal TPR array, answering where in the protein RNA contact occurs.\",\n      \"evidence\": \"Recombinant fragment expression, limited proteolysis, filter-binding and sucrose-gradient assays with SRP RNA mutants\",\n      \"pmids\": [\"15588816\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution geometry of RNA contact not resolved\", \"TPR partner not yet identified biochemically\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the SRP68\\u2013SRP72 interaction interface, showing the N-terminal TPR-like motifs of SRP72 form the SRP68 docking surface.\",\n      \"evidence\": \"Recombinant binding/pulldown assays with defined domain fragments of SRP68 and SRP72\",\n      \"pmids\": [\"16672232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the complex\", \"Stoichiometry and conformational requirements unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Distinguished SRP72-alone RNA contacts from those of the SRP68/72 heterodimer, mapping SRP72 specifically to the 5ef region of the large SRP RNA domain.\",\n      \"evidence\": \"Competitive double-filter binding with 18 SRP RNA helix mutants and purified proteins\",\n      \"pmids\": [\"18347438\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab biochemistry\", \"Functional consequence on targeting not measured\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Pinpointed conserved adenosine A240 in the 5e motif as essential for SRP72 binding, narrowing the recognition determinant to a single helical section.\",\n      \"evidence\": \"Chimeric human/archaeal SRP RNA constructs, site-directed mutagenesis, filter-binding and competition assays\",\n      \"pmids\": [\"18441046\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of A240 recognition inferred, not visualized\", \"Single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved the minimal RNA-binding peptide and the sequence elements (lysine cluster, PDPXRWLPXXER motif, W577) needed for SRP RNA engagement, and modeled the 5e kink-turn.\",\n      \"evidence\": \"Site-directed mutagenesis with binding readout, native PAGE, molecular modeling, chymotryptic mapping\",\n      \"pmids\": [\"21073748\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kink-turn model partly computational\", \"K+ dependence not yet demonstrated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Uncovered a moonlighting nuclear role: the SRP68/72 heterodimer binds the histone H4 tail, occupies chromatin under PRMT control, and can activate transcription, separating this function from the SRP.\",\n      \"evidence\": \"Histone tail peptide pulldown, Co-IP, chromatin association, transcriptional reporter, genome-wide occupancy\",\n      \"pmids\": [\"23048028\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional targets not defined\", \"Mechanism of nuclear versus cytoplasmic partitioning unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked SRP72 to human disease, showing heterozygous mutations in familial aplastic anemia/MDS mislocalize the protein and impair SRP RNA association.\",\n      \"evidence\": \"Mutant construct transfection (localization) and Co-IP of epitope-tagged SRP72 in mammalian cells\",\n      \"pmids\": [\"22541560\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic path from SRP defect to hematopoietic failure unresolved\", \"Limited mechanistic depth, single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided the structural mechanism: SRP72-TPR binds an extended SRP68 motif, and the flexible SRP72-RBD crawls along the 5e/5f loops with a tryptophan forming a K+-stabilized turn while remodeling the ribosome-binding 5f-loop.\",\n      \"evidence\": \"X-ray crystallography of SRP68-PBD/SRP72-PBD and SRP72-RBD/S domain, cryo-EM docking onto ribosome maps\",\n      \"pmids\": [\"27899666\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of RBD crawling during the targeting cycle not captured\", \"Ribosome contacts inferred from docking\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed the conformational logic of heterodimer assembly\\u2014apo-SRP72 is a homodimer whose dissociation and C-terminal cap rearrangement enable SRP68 capture\\u2014and connected cancer-associated residues to interface disruption.\",\n      \"evidence\": \"Crystal structures of apo-SRP72 and SRP68/72 complex, biophysics, mutagenesis, cell co-localization\",\n      \"pmids\": [\"28369529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for homodimer-to-heterodimer transition in cells unknown\", \"Functional role of homodimer state undefined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected SRP72 gene dosage to secretory output in vivo: heterozygous Srp72 loss down-regulates genes encoding secreted factors in hematopoietic cells.\",\n      \"evidence\": \"Srp72 null mouse model, flow cytometry, bone marrow transplantation, gene expression analysis\",\n      \"pmids\": [\"31254415\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No overt hematological phenotype, leaving disease mechanism incomplete\", \"Whether transcriptional changes are direct (chromatin role) or indirect (ER targeting) not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SRP72's cytoplasmic SRP function and its nuclear chromatin/transcriptional function are coordinated, and how either is perturbed to cause bone marrow failure, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mechanism connecting SRP RNA binding defects to hematopoietic disease\", \"Regulation of SRP68/72 nuclear partitioning unknown\", \"Phosphorylation sites and functional consequence of MAPK-dependent modification undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 4, 5, 6]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 10]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\"signal recognition particle (SRP)\", \"SRP68/72 heterodimer\"],\n    \"partners\": [\"SRP68\", \"PRMT1\", \"PRMT5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}